Neuroprotective action of synthetic steroids with oxygen bridge. Activity on GABAA receptor

REY, MARIANA; KRUSE, M. S.; ALVAREZ, LAUTARO D.; GHINI, ALBERTO A.; VELEIRO, ADRIANA S.; BURTON, GERARDO; COIRINI, HéCTOR

EXPERIMENTAL NEUROLOGY

ACADEMIC PRESS INC ELSEVIER SCIENCE

Lugar: Amsterdam; Año: 2013 vol. 249 p. 49 - 58

0014-4886

Allopregnanolone (A) and pregnanolone (P) are able tomodify neural activities acting through the GABAA receptor complex. This capacity makes them useful as anticonvulsant, anxiolytic, or anti-stress compounds. In this study, the performance of seven synthetic steroids (SS) analogous of A or P containing an intramolecular oxygen bridge was evaluated using different assays. Competition assays showed that compounds 1, 5, 6 and 7 affected the binding of specific ligands for the GABAA receptor in a way similar to that of A and P, whereas compoundsA) and pregnanolone (P) are able tomodify neural activities acting through the GABAA receptor complex. This capacity makes them useful as anticonvulsant, anxiolytic, or anti-stress compounds. In this study, the performance of seven synthetic steroids (SS) analogous of A or P containing an intramolecular oxygen bridge was evaluated using different assays. Competition assays showed that compounds 1, 5, 6 and 7 affected the binding of specific ligands for the GABAA receptor in a way similar to that of A and P, whereas compoundsA or P containing an intramolecular oxygen bridge was evaluated using different assays. Competition assays showed that compounds 1, 5, 6 and 7 affected the binding of specific ligands for the GABAA receptor in a way similar to that of A and P, whereas compounds1, 5, 6 and 7 affected the binding of specific ligands for the GABAA receptor in a way similar to that of A and P, whereas compoundsfic ligands for the GABAA receptor in a way similar to that of A and P, whereas compounds 3 and 4 stimulated [3H]-flunitrazepamand reduced [35S]-TBPS binding. The enzyme3â-hydroxysteroid dehydrogenase (3â-HSD) produces the precursor for A and P, and its activity is regulated by steroids. The action of several SS on 3â-HSD activity was tested in different tissues. All SS analyzed inhibit its activity, but compound 5 was the least effective. Finally, the neuroprotective role of two SSwas evaluated in cerebral cortex and hippocampus cultures subjected to hypoxia. Glial fibrillary acidic protein (GFAP) increasewas prevented by A, P, and compounds 3and 4 stimulated [3H]-flunitrazepamand reduced [35S]-TBPS binding. The enzyme3â-hydroxysteroid dehydrogenase (3â-HSD) produces the precursor for A and P, and its activity is regulated by steroids. The action of several SS on 3â-HSD activity was tested in different tissues. All SS analyzed inhibit its activity, but compound 5 was the least effective. Finally, the neuroprotective role of two SSwas evaluated in cerebral cortex and hippocampus cultures subjected to hypoxia. Glial fibrillary acidic protein (GFAP) increasewas prevented by A, P, and compounds 3â-HSD) produces the precursor for A and P, and its activity is regulated by steroids. The action of several SS on 3â-HSD activity was tested in different tissues. All SS analyzed inhibit its activity, but compound 5 was the least effective. Finally, the neuroprotective role of two SSwas evaluated in cerebral cortex and hippocampus cultures subjected to hypoxia. Glial fibrillary acidic protein (GFAP) increasewas prevented by A, P, and compounds 3â-HSD activity was tested in different tissues. All SS analyzed inhibit its activity, but compound 5 was the least effective. Finally, the neuroprotective role of two SSwas evaluated in cerebral cortex and hippocampus cultures subjected to hypoxia. Glial fibrillary acidic protein (GFAP) increasewas prevented by A, P, and compounds 3fibrillary acidic protein (GFAP) increasewas prevented by A, P, and compounds 3 and 5. Only A, P and compound 5 prevented neurofilament (NF160/200) decrease in hippocampus cultures, whereas A and compound 5 partially prevented NF200 and NF160 decreases respectively in cerebral cortex cultures. A preventedmicrotubule associated protein (MAP 2b) decrease in cerebral cortex cultures,while in hippocampus cultures only compounds 3 and 5 had effect. All steroids prevented MAP 2c decrease in both brain regions.5. Only A, P and compound 5 prevented neurofilament (NF160/200) decrease in hippocampus cultures, whereas A and compound 5 partially prevented NF200 and NF160 decreases respectively in cerebral cortex cultures. A preventedmicrotubule associated protein (MAP 2b) decrease in cerebral cortex cultures,while in hippocampus cultures only compounds 3 and 5 had effect. All steroids prevented MAP 2c decrease in both brain regions.A and compound 5 partially prevented NF200 and NF160 decreases respectively in cerebral cortex cultures. A preventedmicrotubule associated protein (MAP 2b) decrease in cerebral cortex cultures,while in hippocampus cultures only compounds 3 and 5 had effect. All steroids prevented MAP 2c decrease in both brain regions.A preventedmicrotubule associated protein (MAP 2b) decrease in cerebral cortex cultures,while in hippocampus cultures only compounds 3 and 5 had effect. All steroids prevented MAP 2c decrease in both brain regions.3 and 5 had effect. All steroids prevented MAP 2c decrease in both brain regions.